Guanidinoalkylbenzodioxan derivatives

ABSTRACT

THE PREPARATION OF A GROUP OF NEW COMPOUNDS HAVING ANTIHYPERTENSIVE ACTIVITY AND CHARACTERIZED BY BEING GUANIDINOALKYL-1,4-BEBENZODIOXANS. THE COMPOUNDS ARE MOST EASILY PREPARED BY REACTING A 2-AMINOALKYL-1,4-BENZODIOXANE WITH CYANAMIDE.

United States Patent 3,829,441 GUANIDINOALKYLBENZODIOXAN DERIVATIVESJohn Nicholson Gardner, Wayne, N.J., assignor to Smith Kline & FrenchLaboratories, Philadelphia, Pa. No Drawing. Continuation-impart ofapplication Ser. No.

251,471, Jan. 15, 1963, now Patent No. 3,360,529, dated Dec. 26, 1967.This application Nov. 1, 1967, Ser. No. 679,670 Claims priority,applicationi/regt Britain, Jan. 29, 1962,

9 The portion of the term of the patent subsequent to Dec. 26, 1984, hasbeen disclaimed Int. Cl. C07d 15/18 US. Cl. 260-3403 1 Claim ABSTRACT OFTHE DISCLOSURE The preparation of a group of new compounds havingantihypertensive activity and characterized by beingguanidinoalkyl-1,4-benzodioxans. The compounds are most easily preparedby reacting a Z-aminoalkyl-1,4-benzodioxane with cyanamide.

This application is a continuation-in-part of my copending application,Ser. No. 251,471 filed Jan. 15, 1963, now Pat. No. 3,360,529, issuedDec. 26, 1967.

This invention relates to new 1:4-benzodioxan derivatives havingpharmacodynamic activity.

More specifically, the compounds of this invention are guanidinoalkyl-l:4-benzodioxans illustrated by the following structural formula:

R1 8 0 R5 Re IFIH in which R and R are hydrogen, halogen such as fluoro,

bro-mo or chloro; lower alkyl such as methyl or ethyl;

lower alkoxy such as methoxy or ethoxy; R R are hydrogen or lower alkyl.

The object of the present invention is a group of compounds illustratedby the following formula:

R l l in which R is hydrogen, lower alkyl, lower alkoxy, halo or nitro;R is hydrogen or, when R is lower alkyl, lower alkyl; and R and R are,respectively, hydrogen or lower alkyl.

The generic group of compounds of this invention is characterized byhaving the basic guanidinoalkyl-1,4-benzodioxan nucleus which impartsantihypertensive activity to such compounds. The substituents on thebasic structure may be any of those common to the art, such as thosedisclosed in US. Pat. No. 2,979,511 without changing the qualitativehypotensive activity of these compounds.

The compounds of this generic invention demonstrate antihypertensiveactivity by blockage of adrenergic nerve after intravenousadministration of doses of 5-25 mg./ kg. in the standard chloraloseanesthetized dog procedure. As a further example of the basicpharmacological activity of this series, the most simple member of theseries, 2-guanidinornethylbenzodioxan, exerts antihypertensive activityin the neurogenic hypertensive dog at 20 mg./kg., orally. Furtherquantitative properties of this group of compounds will be elaborated onhereafter.

3,829,441 Patented Aug. 13, 1974 ice Formula 2 in which R isrespectively hydrogen or methyl.

Preferred individual compounds are the bases,2-guanidinomethyl-l:4-benzodioxan, 2-1' guanidinoethyl 1:4- benzodioxan,5 28-dimethyl-Z-guanidinomethyl 1:4 benzodioxan and 5:8-dimethyl-2-l'-guanidinoethyl-1:4-benzodioxan and theirpharmaceutically acceptable salts.

Certain of the compounds of this invention contain one or moreasymmetric carbon atoms and, therefore, can exist in the form of opticalisomers. Such isomers and their salts are included in this invention asare other posi tion isomers, together with other structural variationsobvious to one skilled in the art. The terms lower alkyl, lower alkoxyor carbalkoxy are used to define moieties having a maximum of 3 carbonatoms.

The compounds of this invention are most easily prepared by reacting anamine or its salt having the basic general formula:

R1 0 R5 a -NH1 R, I t

Formula 3 in which R -R are as defined, with cyanamide or with acompound in which X represents a replaceable group which will react withthe amino group of Formula 3. Examples of the second reactant areS-methylisothiouronium salts, O- methylisouronium salts and1-amidino-3:S-dimethylpyrazole. The end products are most convenientlyisolated as their acid salts. Other pharmaceutically unacceptable saltsare useful in such isolation procedures and can be thereafter convertedto nontoxic salts for use.

The amine intermediates of Formula 3 are prepared by methods well-knownto the art as illustrated by the working examples. Briefly, thesecompounds are prepared (1) by reacting an optionally substitutedcatechol with an optionally substituted epichlorhydrin to give thealcohol which is in turn converted into the desired amine or (2) byreacting the catechol with a reactive 1,2-dihalo compound thenconverting to the amine. These reactions are well illustrated hereafter.

The new 1:4-benzodioxan derivatives of the invention have been found toexhibit varied pharmacological activity in the animal body. Thuscompounds falling within the definition of Formula 1 have been found toexercise pharmacological actions on the peripheral nervous system,particularly on the sympathetic and parasympathetic nervous 3 systems.For instance, some of the compounds such as 2-1'-guanidinoethyl 1:4benzodioxan have 'very pronounced adrenergic nerve blocking activity,some such as 5: S-dimethyl-2'-guanidinomethyl-1:4-benzodioxan havepronounced ganglion blocking activity and antihistaminic activity. Allhave these activities to a certain degree.

For practical use, the pharmacologically active compounds of theinvention are made up into compositions containing at least one of saidcompounds as the essential active ingredient in amount sufficient toproduce the desired therapeutic effect, the active ingredient generallybeing in association with one or more pharmaceutical diluents and/orexcipients therefor. The compositions can be made up in a dosage unitform adapted for the desired mode of administration which may be oral orparenteral. Thus the dosage may be a tablet, pill, capsule, or a sterilesolution or suspension for parenteral administration.

The following examples illustrate the invention.

EXAMPLE 1 2-Aminomethyl-1:4-benzodioxan hydrochloride (8 g., B'ovet etal., Arch. intern. pharmacodynamic 55, 15 (1937)) and cyanamide (8 g.)in water (16 cc.) are heated under reflux for 24 hours. The reactionmixture is cooled at C. for several hours, filtered and the solid on thefilter washed with ice-cold water cc.). The filtrate and washings arewarmed to 50 C. and potassium bicarbonate (8 g.) added. The guanidinebicarbonate which separates on cooling is isolated and suspended inwater (32 cc.) at 50 C. Nitric acid (50%) is added dropwise until thesolution is acidic and on cooling to 0 C. the nitrate ofZ-guanidinomethyl-l :4-benzodioxan (7.6 g.) separates as colorlesscrystals, m.p. 164-165 C. after recrystallization from water.

EXAMPLE 2 Catechol (103 g.) and anhydrous potassium carbonate (70 g.) ingently refluxing acetone are treated, by dropwise addition, with3:4-dibromobutan-2-one (35 cc.). After addition of the 3:4-dibromobutan-2-one a further 70 g. of potassium carbonate are addedin a single lot, followed by further slow addition of the ketone (35-cc.). This process is repeated a further three times with 60 g. ofpotassium carbonate and 35 cc. of the ketone being used each time. Oncompletion of the additions, reflux is maintained for 20 hours. Theresulting mixture is then cooled and filtered. The filtrate isconcentrated, diluted with water and the product isolated by etherextraction. Distillation of the extracts gives 2-acetyl1:4-benzodioxan(77 g.), b.p. 88 C. (0.05 mm.) which when crystallized from aqueousmethanol has a m.p. of 3435 C.

The reaction of 2-acetyl-1z4-benzodioxan (61.5 g.) with hydroxylaminehydrochloride (36 g.) and sodium acetate (110 g.) refluxed in 50%aqueous ethanol (600 cc.) gives, after concentration, ether extractionand distillation, 2-acetyl-1z4-benzodioxan oxime (65 g.), b.p. 123-124C. (0.4 mm.).

The 1:4-benzodioxan oxime (41 g.) in ether (185 cc.) is added to asuspension of lithium aluminum hydride (30 g.) in ether (1050 cc.) andthe mixture refluxed for 24 hours. Ethanol-ether (1:1) is used todestroy the excess hydride, and then saturated sodium sulphate is addeduntil the solids form a paste. The ether is decanted, extracted with 2NHCl, and the acid solution is basified with solid sodium carbonate andsome 2N NaOH. Ether extraction and distillation gives2-1'-aminoethyl-1:4-benzodioxan (39 g.) b.p. 140150 C. (14 mm.).

The 2-l'-aminoethyl-1:4-benzodioxan g.) in ether is treated with excessisopropanolic-hydrogen chloride and the resulting2-l'-aminoethyl-1:4-benzodioxan hydrochloride (11.5 g.) isolated byfiltration. After crystallization from methanol-di-isopropyl ether thehydrochloride has a m.p. of 2l9220 C.

The 2-l'-aminoethy1-1:4-benzodioxan hydrochloride (5 g.) and cyanamide(5 g.) in water (15 cc.) are heated at reflux for 24 hours. Theresulting solution is cooled at 0 C. for two hours, filtered, and thefiltrate made alkaline with potassium bicarbonate. An oil separates andon addition of nitric acid (1 part conc. HNO to 1 part water) to themixture until the solution is acidic, the oil slowly crystallizes.Isolation of this solid and repeated crystallization of it from mixturesof ethanol, methanol, ethyl acetate and hexane gives two isomers of2-l-guanidinoethyl-1:4-benzodioxan nitrate, one having a m.p. of 177-179 C. and the other having a m.p. of 144146 C. Both forms crystallizeas prisms.

EXAMPLE 3 3:6-Dimethylcatechol (26 g.) in acetone (300 cc.) is treatedwith anhydrous potassium carbonate (75 g.) and 3:4-dibromobutan-2-one(52 g.) in the manner described in Example 2, the addition of carbonateand ketone being made in four equal portions. The desiredZ-acetyl-5z8-dimethyl-1:4-benzodioxan (9.9 g.) is isolated in the mannerdescribed in Example 2 and has a m.p. of 4849 C., 87- 89 C. (0.4 mm.).

The isolated ketone (8.6 g.), hydroxylamine hydrochloride (4.5 g.),sodium acetate (15 g.) and 50% aqueous ethanol cc.) are heated at refluxfor two hours and cooled at 0 C. The resulting2-acetyl-5:8-dimethyl-1:4-benzodioxan oxime separates as needles (7.1g.) and after crystallization from ether-hexane has a m.p. of 1l7 C.

The oxime (5.1 g.) in ether (60 cc.) is reduced with lithium aluminumhydride (2.7 g.) in ether 100 cc.) as described in Example 2 to give2-1-aminoethyl-5:8-dimethyl-1:4-benzodioxan (4.0 g.), b.p. 1l8120 C.(1.25 mm.).

The foregoing amine (639 mg.) in ether (20 cc.) with excessisopropanolic hydrogen chloride gives the amine hydrochloride (450 mg),m.p. 272277 C. after crystallization frommethanol-isopropanol-di-isopropyl ether.

The amine hydrochloride (350 mg.) is heated under reflux in water (10cc.) with cyanamide (750 mg) for 24 hours. The resulting solution iscooled and, after washing with ether, made alkaline with potassiumbicarbonate. A gum precipitates and crystallizes very slowly. The solidobtained is isolated, suspended in 15 cc. of water and the resultingsuspension made acid with 2N H SO The solid dissolves and on cooling thedesired 5 :8-dimethyl-2-1- guanidinoethyl-l:4-benzodioxan sulphate isobtained as plates, m.p. 223-230" C.

EXAMPLE 4 3:6-Dimethylcatechol (36 g.) in acetone (250 cc.) is reactedwith anhydrous potassium carbonate 104 g.) and ethyl,a,B-dibromopropionate (78 g.) in a manner similar to that described inExample 2, the addition of ester and carbonate being made in four equalportions. The desired 2 carbethoxy 5:8 dimethyl 1:4 benzodioxan has ab.p. of 100 C. (0.25 mm.).

The foregoing ester (15 g.) is shaken with excess am monia solution for4 hours and the resulting solid 5:8- dimethyl 1:4 benzodioxan 2carbonamide 12.9 g.) isolated by filtration. The amide has a m.p. of 121C. after crystallization from light petroleum (b.p. 6080 C.).

The foregoing amide (11.8 g.) in ether (50 cc.) is reduced with lithiumaluminum hydride (5 g.) in ether (250 cc.) by the method described inExample '2. On extraction of the initial ethereal solution with 2N HCl,5 :S-dimethyl 2 aminomethyl 1:4-benzodioxan hydrochloride (10.8 g.)separates and is collected and recrystallized from methanol-water toyield crystals having a m.p. of 254- 255 C.

The foregoing hydrochloride (2.5 g.) and cyanamide (2.5 g.) are heatedunder reflux in 10 cc. water for 24 hours, then cooled at 0 C. for twohours and filtered. Potassium bicarbonate is added to the resultingfiltrate at 50 C., thereby precipitating 5:8 dimethyl 2guanidinomethyl-1:4-benzodioxan bicarbonate, which is filtered ofi,

re-suspended in 10 cc. of water at 40 C., acidified with diluted (1:1)nitric acid and cooled to C. The nitrate of the above-mentioned compoundcrystallizes out and is further recrystallized from water, m.p. 150-151"C.

The intermediate amine :8-dimethyl-Z-amino-methyl- 1:4-benzodioxan isalso prepared by the following alternative method.

3:6 Dimethylcatechol (16.5 g.), epichlorhydrin cc.) and 12% potassiumhydroxide (50 cc.) are heated together at 60 C. under an atmosphere ofnitrogen in a sealed flask for 20 hours. The reaction mixture is thencooled and extracted with ether. After washing with 2N NaOH and water,the etheral solution is dried over magnesium and evaporated.Distillation of the residue yields 5:8 dimethyl 2 hydroxymethyl 1:4benzodioxan, b.p. 110-120 C. (0.5 mm.). This alcohol (5 g.) is heated at0 C. with phosphorous tribromide (1.8 cc.) and allowed to stand at roomtemperature for three days. The reaction mixture is poured on to ice andthe reaction product extracted with dichloromethane. Evaporation of thesolvent and distillation gives 2 bromomethyl 5 :8dimethyl-1:4-benzodioxan (2.4 g.), b.p. 92 C. (0.2 mm), 1.6 g. of whichare heated with excess 12% ethanolic ammonia in a steel bomb at 120 C.for 18 hours. The ethanol is evaporated. The residue is treated with 2NHCl, washed with ether, and basified with 2N NaOH. The resulting amineis extracted into ether and on shaking with 2N HCl the desired 5 :8dimethyl 2 aminomethyl- 1:4-benzodioxan hydrochloride (0.26 g.)separates and is collected, m.p. 254-255 C.

EXAMPLE 5 An equimolar quantity of 7 chloro 2 aminomethyl- 1:4benzodioxan hydrochloride [Marini-Bettolo et al., Croat. Chem. Acta 29,363 (1957)] is substituted for the amine in Example 1 to give, withsulfuric acid, 2- guanidinomethyl-7-chloro-1:4-benzodioxan sulfate.

7 Methoxy and 7 nitro 2 aminomethyl 1:4- benzodioxan salts (samereference) give respectively 2- guanidinomethyl 7 methoxy 1:4benzodioxan nitrate and 2 guanidinomethyl 7 nitro 1:4 benzodioxannitrate.

2 3' Aminopropyl 1:4 benzodioxan hydrochloride [Landi-Vittory et al.,Rend. ist. super. sanita 22, 217 (1959)] gives 2 3' guanidinopropyl 1:4benzodioxan nitrate.

2 Aminomethyl 3 methyl 1:4 benzodioxan (Koo, J. et a1., Chem. & Ind.1958, 832) gives Z-guanidinomethyl- 3-methyl-l :4-benzodioxanhydrochloride.

What is claimed is:

l. A compound selected from the group consisting of a base of theformula:

and a nontoxic, pharmaceutically acceptable acid addition salt thereof,wherein R is a member of the group consisting of hydrogen, methyl,methoxy, chlorine and bromine.

References Cited UNITED STATES PATENTS 3,360,529 12/1967 Gardner260-3403 DONALD G. DAUS, Primary Examiner J. H. TURNIPSEED, AssistantExaminer U.S. Cl. X.R. 424278

